Antiemetic compositions

ABSTRACT

An antiemetic pharmaceutical composition for use in conjunction with  oncoical chemitherapy. The composition is of special value in pediatric oncological medicine. The active ingredient is Δ-8-tetrahydro-cannabinol, Δ-8-THC. Average unit dosage forms for use in pediatric medicine contain from about 4 mg/m 2  to about 20 mg/m 2  of the active compound.

This application is a 371 of PCT/EP93/01335, filed May 27, 1993.

The present invention relates to antiemetic pharmaceutical compositionsfor use in human medicine, and more particularly in pediatric oncologicmedicine. The drugs are of special value as antiemetic in pediatriconcology.

Cannabis has been used for millenia as antiemetic. After theidentification of delta-9-tetrahydro-cannabinol (delta-9-THC), as thepsychoactive constituent of cannabis, it was evaluated as anti-vomitingagent. It was found useful as antiemetic in the chemotherapy of cancer,and is marketed today commercially under the name of Dronabinol. It hasa limited effectivity, and prevents vomiting and nausea in about 20 to30 per cent of treated patients, and reduces such symptoms in another 40to 50 per cent, having little or no effect in the rest. Pronounced sideeffects are drowsiness, dizziness and in some cases--anxiety. Suchsymptoms are pronounced with elderly patients, while younger onesundergo mainly mood changes.

J. Pharm. Sci., 1972, vol. 61, pages 1106 to 1112, describes the oraland parenteral use of marijuana constituents.

Int. J. Pharmaceutics, 1988, vol. 43, pages 9 to 15, describes the skinpermeation behaviour of tetrahydrocannabinol through rat and human skinin vitro.

J. Natl. Cancer Inst., 1975, vol. 55, p. 597 to 602, is a generalarticle dealing with anti-cancer therapy based on cannabinoids.

The invention relates to pharmaceutical antiemetic compositions for useas a highly effective antiemetic agent in children undergoing cancertherapy.

The compositions of the invention comprise as active ingredient aneffective quantity of delta-8-THC, of the formula(I) ##STR1##

This compound is an isomer of delta-9-THC, and has been found to be atleast as effective for the intended use as delta-9-THC, but hasconsiderably reduced side-effects, especially in pediatric medicine. Thecompound delta-8-THC is considerably more stable towards variouschemicals than the delta-9 isomer, and is less prone to oxidation.Furthermore, it can be produced easily and is less expensive than thedelta-9-THC isomer.

There administration is per os, and various dosage forms were prepared.

The compositions of the invention were tried on patients, mainlychildren, before the administration of a variety of anti-cancer drugs.In all of these causes of nausea and vomiting, the compositions provedhighly effective, and had negligible undesired side-effects. Theexperiments were carried out in the framework of an open labelevaluation and results indicate that this composition is by far superiorto existing ones.

The dosage administered is in the range of from about 5 mg to 20 mg, andpreferably in the range of from 6 mg to about 15 mg. In oncology(pediatrics) the dosage is about 4 mg/m² to about 30 mg/m², andpreferably about 10-18 mg/m² (surface area of the skin).

It was found that there can be administered to children doses which arelarger than those which causes pronounced side-effects in adults. Inpediatric use, essentially no side effects of significance wereencountered. Doses of the order of 18 mg/m² did not cause undesiredside-effects.

The effective component is generally administered in a vehicle such asan edible oil. Preferably the active compound is at least 80 per centpure.

In a trial, with 8 children of 3 to 13 years age, with various bloodcancers, treated with a variety of antineoplastic drugs, 18 mg/m², inedible oil, p.o. of delta-8-THC was given two hours before theantineoplastic drug, and repeated every 6 hours of 24 hours. Vomitingwas completely prevented, with negligible side effects. So far thesechildren have received Δ⁸ -THC nearly 500 times (see Table).

PATIENTS AND METHODS

Eight children with various blood cancers were administered delta-8-THCat a dose of 18 mg/m² p.o. two hours before the start of the anticancertreatment. The drug was dissolved in corn or olive oil (6 mg/ml). Thesame dose was repeated every 6 hrs for 24 hrs. The treatment for eachchild is presented in the Table. Whenever additional cycles ofantineoplastic therapy were required, delta-8-THC was administeredfollowing the same time procedure described above. Children receiveddelta-8-THC only during days when emetogenic drugs were administered.

Established anticancer drug protocols were followed with all patients.

A study on vomiting due to antineoplastic therapy was carried out with 8patients. Details of their antineoplastic treatment and side effects ofthe antiemetic therapy are presented in the Table. Chemotherapyprotocols of the types indicated in the Table almost invariable causeintense vomiting, which starts about 2 hrs after the initiation ofchemotherapy and gradually ends over a 24 hr period. In preliminarytrials we tried to end the antiemetic therapy after the first or seconddose of the cannabinoid, i.e. after 6 or 12 hrs. Vomiting started inmost cases. Hence, in the recorded trial, all children were given 4doses over 24 hrs. When antiemetic protocol described above was strictlyfollowed no emesis was noted. In one case (patient D.E.) delta-8-THCtherapy initially was refused. The patient experienced debilitatingvomiting for 24 hrs after the antineoplastic treatment. During thesecond treatment cycle (which took place after 8 days), at the patient'sfamily request, delta-8-THC treatment was initiated. No vomitingoccurred.

As indicated in the Table the side effects observed with delta-8-THCwere minor: some irritability as slight euphoria. No anxiety orhallucinogenic effects were noted in spite of the high dosesadministered.

The LD₅₀ values for Fischer rats treated orally with single doses ofdelta-9-THC and delta-8-THC, and observed for 7 days, are 1910 mg/kg and1980 mg/kg (for males) respectively and 860 mg/kg (for females). Thehistopathological changes caused by these extremely high doses wereessentially the same for both delta-8- and delta-9-THC. LD₅₀ could notbe determined in either rhesus monkeys or dogs as single oral doses ofup to 9000 mg/kg of either delta-8- or delta-9-THC in dogs or monkeyswere non lethal. Histopathological alterations did not occur in eitherdogs or monkeys.

We found that infants and young children with different blood cancers,who were treated with a variety of anticancer drugs protocols could beadministered doses of delta-8-THC considerably higher than the doses ofdelta-9-THC generally administered to adult cancer patients without theoccurrence of major side effects (5-10 mg/m² of delta-9-THC generallyrecommended for adult patients versus 18 mg/m² of delta-8-THC used by usin children). Our antiemetic protocol for cancer patients, to which westrictly adhere, consists of one dose of delta-8-THC (18 mg/m²) 2 hoursbefore chemotherapy, followed by the same dose every 6 hours for a totalof 4 doses per day. As mentioned above, the prevention of vomiting wascomplete regardless of the antineoplastic protocol followed.

                                      TABLE                                       __________________________________________________________________________    Delta-8-THC Administered to Children Treated for Various Blood                Cancers..sup.a                                                                         Age,                      Number and                                          (years),       Antineoplastic                                                                           Effect of                                  No. Name sex   Diagnosis                                                                              treatment  antiemetic treatments                      __________________________________________________________________________    1.* A. M.                                                                              10    A.L.L..sup.b pre B,                                                                    Cytarabine-                                                                              (32), no side effects                               m     in relapse                                                                             L-Asparaginase.sup.c                                  2.  C. O.                                                                                3.5 Hodgkin's                                                                              MOPP-ABV   (64), slight irritability                           m     disease  protocol.sup.d                                                                           during first 2 cycles                      3.  L. H.                                                                              4     A.L.L.,  BFM protocol.sup.e                                                                       (76), slight irritability                           f     T type              and euphoria                               4.  M. H.                                                                              3     Wilm's tumor,                                                                          NWTS-4     (30), no side effects                               f     stage III                                                                              protocol.sup.f                                        5.  R. M.                                                                              13    A.L.L. T type                                                                          Cytarabine,                                                                              (24), no side effects                               f     in second relapse                                                                      Amsacrine protocol.sup.g                              6.**                                                                              D. E.                                                                              7     Burkitt's                                                                              Burkitt's lymphoma                                                                       (114), no side effects                              m     lymphoma protocol.sup.h                                        7.***                                                                             K. K.                                                                              6     A.L.L.   Rez BFM 87 (64), no side effects                               f              protocol.sup.i                                        8.  A. A.                                                                              5     A.L.L.   BFM protocol.sup.e                                                                       (76), no side effects                               m                                                                    __________________________________________________________________________     *Metoclopromide (0.3 mg/kg) p.o. or i.v. in previous treatment failed to      prevent vomitting                                                             **During first cycle, refusal to take THC caused profuse vomiting             ***Treatment during remission after 2nd relapse and during 3rd relapse.       Footnotes to Table                                                            .sup.a. Δ -- THC, 18 mg/m.sup.2                                         .sup.b. A.L.L. -- acute lymphoblastic anemia                                  .sup.c. Cytarabine and asparaginase                                           .sup.d. Includes vincristine, procarbazine, doxorubicin, bleomycin,           vinblastine                                                                   .sup.e. Includes vincristine, daunorubicine, asparaginase,                    cyclophosphamaide, cytarabine, 6meracaptopurine etoposide, methotrexate       .sup.f. Includes vincristine, doxorubicin, dactinomycin                       .sup.g. Cytarabine and amsacrine                                              .sup.h. Includes vincristine, doxorubicin, cyclophosphamide, methotrexate     .sup.i. Includes 6mercaptopurine, vincristine, methotrexate, cytarabine,      teniposide, asparaginase                                                 

We claim:
 1. A method for treating emesis in children undergoinganticancer chemotherapy which comprises orally administering to saidchildren an effective amount of the compound of formula 1 ##STR2##
 2. Amethod according to claim 1, in a form suitable for oral administration.3. A method according to claim 2, wherein the active compound isadministered with an edible oil.
 4. A method according to claim 1,wherein the quantity comprises from 2 to 20 mg as total quantity of thecompound of the formula (I).
 5. A method according to claim 4, whereinthe dosage is between 3 to 15 mg as total quantity of the activecompound.
 6. A method according to claim 1, wherein the active compoundis at least 80 per cent pure.